DIAN-TU treatment trial

Dr Christopher Lane

Clinical Research Associate, Dementia Research Centre

Overview

• What has the DIAN –L study taught us?• DIAN – TU – the treatment trial

– The rationale– Who is eligible– What is involved

Dominantly Inherited Alzheimer Network

• International observational trial (US, UK, Australia) started 2011• Patients with a family history of dominantly inherited Alzheimer’s

disease • Both at risk and affected participants (>280; 33 DRC)• Biomarker study (Blood, CSF)• Imaging• Clinical assessment• Only UK site - Dementia Research Centre, NHNN, Queen Square

•Courtesy of Tammie Benzinger and Tyler Blazey

Amyloid deposition may begin at least 15 years prior to dementia onset in mutation carriers

Motivation for prevention studiesCompleting/Completed

Phase III trialsNewer

Phase II/III trialsPrevention

studies

http://adni.loni.ucla.edu/about/biomarkers/

Current therapeutic trials may be too late: proposed therapeutics for Alzheimer’s disease currently target slowing or halting the underlying disease (disease modifying), but are not likely to

reverse the extensive neuronal death present at the onset of symptoms.

There is certain risk (~100% with known mutation in PS1, PS2 or APP) of the disease which enables prevention studies and

increases the power of treating minimally symptomatic patients.

Disease modifying therapeutics are largely developed with animal models based on human disease causing mutations. Thus, AD caused by known autosomal dominant mutations is most likely to respond to these proposed disease modifying treatments.

Results from treatment trials in autosomal dominant AD will bridgecellular and mouse therapeutic research with sporadic AD therapeutic research.

Rationale for treatment trials in individuals at risk for Autosomal Dominant Alzheimer’s disease

Treatment approach

• Immunotherapy approach- Using drugs that stimulate the immune

system in order to remove abnormal proteins that have been deposited

- Many current studies use monoclonal antibodies - bind to proteins and stimulate the immune system in order to remove amyloid

DIAN TU trial

• Aim: To assess the safety, tolerability and biomarker efficacy of gantenerumab and solanezumab in subjects who are known to have an Alzheimer's disease causing mutation.

What’s the treatment?

• Two different treatment options • Both monoclonal antibodies that bind to amyloid (abnormal

protein) in the brain and remove it– Solanezumab (given by infusion)– Gantenerumab (given by subcutaneous injection)

• Monthly treatment• Participants randomly assigned to either treatment option• May get placebo (dummy) drug (3:1 chance of getting active

drug in mutation positive participants)• Two year duration

Who’s eligible?

• Age 18 years and above• Be ‘at risk’ for Familial AD (have a first degree relative with

a known disease-causing mutation)• Be -15 years to +10 years from predicted age of onset of

symptoms• Can be asymptomatic or mildly affected• Does NOT need to know mutation status and does NOT

need to learn status to participate

DIAN TU trial – what will it entail?

• Annual visit– Clinical assessments– Cognitive testing– MRI scan– PET scanning (at UCLH and Cambridge)– Blood tests– Lumbar puncture– Collateral source questionnaires

DIAN TU trial – what will it entail?

• Monthly visits to the DRC• Depending on the drug arm, participants will receive either a monthly

subcutaneous injection or intravenous infusion

FAQs

• Can participants taking medications for memory impairment (e.g. donepezil) remain on their medications during trial participation?Yes, but we ask that the dose stays the same. You would discuss this with the study nurse.

FAQs

• Who decides whether participants get the active drug or placebo?A computer system randomly assigns participants to active drug or placebo. The assignment to drug or placebo is “blinded” which means neither the participant nor any member of the study team will know whether the individual is receiving the study medication or placebo. All mutation negative participants will be assigned to placebo for safety purposes.

FAQs

• Will the study personnel know participants’ genetic status?No. Genetic status of participants will not be known by study personnel. Participants will remain blinded to their genetic status unless they have previously found this out. If participants wish to know their gene status, they will be referred for genetic counselling. Participants who know that they are gene negative are not eligible.

FAQs

• If you have side effects from a drug, does mean that you are mutation positive?No. Even people on placebo may have side-effects. A side effect is likely to be mild and may not be different from everyday type discomforts such as headache, fatigue and nausea. All side effects that you experience will be documented.

DIAN Expanded Registry

Provides an overview of Autosomal Dominant Alzheimer’s disease

(ADAD), links to other web resources (alzforum.org).

Operational as of Feb 2012

Posts of past webinars

Register an interest in participation in DIAN-TU

Contact details• Dr Chris Lane (Clinical Research Fellow) – c.lane@ucl.ac.uk• Jane Douglas (Clinical Trials nurse) – jane.douglas@ucl.ac.uk or 02034483560

Any questions?